The focus of this project is to examine physiological and cellular mechanisms that regulate human skeletal muscle growth. Maintenance of an adequate muscle mass is critical not only for mobility and energy/protein metabolism, but also for survival. Muscle mass is maintained or increased only when adequate anabolic stimuli counteract the protein catabolism that characterizes the basal state and many of the conditions that lead to muscle wasting. Our preliminary studies have shown that nutrition and resistance exercise are two major anabolic stimuli for skeletal muscle. During the previous grant cycle we have shown that the mTOR signaling pathway appears to be an involved in both the resistance exercise and nutrient stimulation of muscle protein synthesis in humans. We have also shown that the mTOR pathway is activated following a novel treatment (blood flow restriction during low-intensity resistance exercise). This finding has potential use in patient populations (e.g., in patients undergoing physical therapy following surgery, frail elderly, orthopedic patients, etc.) that cannot perform resistance exercise at the intensity level needed to induce muscle growth. Therefore, based on our preliminary data, our general hypothesis is that anabolic nutrients, metabolic stress/reactive hyperemia, and age are independent factors that can regulate anabolic signaling, anabolic and catabolic gene expression, and muscle protein synthesis following a bout of resistance exercise. Specifically, we hypothesize that in healthy human subjects: (1) Activation of the mTOR signaling pathway is the primary cellular mechanism responsible for the stimulation of muscle protein synthesis following resistance exercise and/or anabolic nutrient ingestion. (2) Blood flow restriction during low-intensity resistance exercise induces muscle metabolic stress and reactive hyperemia which activates anabolic pathways. (3) Aging is associated with a reduced anabolic response to resistance exercise, and this defect can be overcome by post-exercise ingestion of anabolic nutrients and/or the novel treatment of blood flow restriction. These acute studies will provide insight into physiological and cellular mechanisms that regulate human muscle protein balance, and will be utilized as a basis from which to develop scientifically-based interventions for improving muscle protein balance in conditions such as aging, rehabilitation, trauma, cancer, and AIDS. PUBLIC HEALTH RELEVANCE: The focus of this project is to examine how nutrients and resistance exercise regulate human muscle growth. In this application we propose several human studies to: 1) determine whether a key cellular pathway (mTOR) is responsible for controlling muscle growth; 2) examine the mechanisms of how a novel exercise treatment with potential clinical significance can promote muscle growth; 3) determine whether the muscle growth response can be improved in the elderly with the use of nutrient supplementation following exercise. These studies will provide insight into the mechanisms that regulate human muscle growth, and will be used as a basis from which to develop scientifically-based interventions for improving muscle growth and function in conditions such as aging, rehabilitation, trauma, cancer, and AIDS.